Part 1. Overview Information

Key Dates

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

The BRAIN Initiative: The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is aimed at revolutionizing our understanding of the human brain. By accelerating the development and application of innovative technologies, researchers will be able to produce a new dynamic picture of the brain that, for the first time, will show how individual cells and complex neural circuits interact in both time and space. It is expected that the application of these new tools and technologies will ultimately lead to new ways to treat and prevent brain disorders.

NIH is one of several federal agencies involved in the BRAIN Initiative. Planning for the NIH component of the BRAIN Initiative is guided by the long-term scientific plan, BRAIN 2025: A Scientific Vision, which details seven high-priority research areas and calls for a sustained federal commitment of $4.5 billion over 12 years. This Funding Opportunity Announcement (FOA) is based on careful consideration by the NIH of the recommendations of the BRAIN 2025 Report, and input from the NIH BRAIN Multi-Council Working Group. Videocasts of the NIH BRAIN Multi-council Working Group are available at http://www.braininitiative.nih.gov/about/mcwg.htm.

To enable rapid progress in development of new technologies as well as in theory and data analysis, the BRAIN Initiative encourages collaborations between neurobiologists and scientists from statistics, physics, mathematics, engineering, and computer and information sciences; and NIH welcomes applications from investigators in these disciplines.

NIH encourages BRAIN Initiative applications from investigators who are underrepresented in the biomedical, behavioral, or clinical research workforce (see data and the most recent report on Women, Minorities, and Persons with Disabilities in Science and Engineering). Such individuals include those from underrepresented racial and ethnic groups, those with disabilities, and those from disadvantaged backgrounds.

NIH also encourages businesses to participate in the BRAIN Initiative. It is possible for companies to submit applications directly to BRAIN Initiative program announcements or to collaborate with academic researchers in joint submissions.Small businesses should consider applying to one of the BRAIN Initiative small business Funding Opportunity Announcements (FOAs).

In addition to the National BRAIN initiative, the NIH continues to have a substantial annual investment in neuroscience research. The Institutes and Centers contributing to the NIH BRAIN Initiative support those research efforts through investigator-initiated applications as well as through specific FOAs. Potential applicants to this FOA are strongly encouraged to contact Scientific/Program staff if they have any questions about the best FOA for their research.

The BRAIN Initiative will require a high level of coordination and sharing between investigators. While this FOA does not use a cooperative agreement mechanism, it is expected that the awardees will align their research with the BICCN goals, and coordinate their activities by participating in the BICCN meetings and other BRAIN Initiative activities.

The BRAIN Initiative Cell Census Network (BICCN)

The BRAIN Initiative Cell Census Program awarded 9 projects in 2017, 5 in 2018, and 8 in 2019 under a group of FOAs (RFA-MH-17-210,-215,-225, and -230, RFA-MH-19-148, and -149), which collectively constitute the BICCN). The overarching goal of the BICCN is to generate comprehensive 3D common reference brain cell atlases that will integrate molecular, anatomical, functional, and cell lineage data for describing cell types in mouse, human, and non-human primate brains.

The expected outcomes of the BICCN include:

• fundamental knowledge on diverse cell types and their three dimensional organizational logic in the brain;
• an open-access 3D digital brain cell reference atlas with molecular, anatomical, and physiological annotations of brain cell types in mouse;
• a comprehensive neural circuit diagram in mouse brain;
• reagents for cell-specific targeting;
• validated high throughput and low-cost approaches to characterizing cell diversity in human and/or non-human primate brain samples.

The BICCN operates as a cooperative network to promote collaboration and coordination among the projects within the Network and the BRAIN Initiative, as well as with any external research entities that have similar goals. Currently, the BICCN has established close collaboration and coordination relationship with BRAIN Initiative Informatics Infrastructure projects funded under RFA-MH-17-255, RFA-MH-17-256, RFA-MH-257 and reissues of those FOAs. It is expected that the BICCN awardees and their collaborators will work together to achieve the common goals. This will involve regular meetings and other coordinated activities within the BICCN as well as the BRAIN Initiative and more broadly with the research and education communities. Thus, the BICCN will leverage existing atlases and common coordinate systems to facilitate collaborative efforts for the data annotation and 3D spatial mapping.

Common Coordinate Systems

A large amount of data concerning brain anatomy and physiology exists and continues to grow rapidly. With the advent of single-cell omics technologies, new biomolecular data are expected to flourish, adding to the existing expansion of data sets. Correspondingly, there is an increasing need to enhance data interoperability and harmonization among data producers and data accessibility to the broad research community, and to reduce unnecessary repetition in data generation. Atlases and common coordinate systems play a fundamental role in gathering, analyzing, communicating, and standardizing data. The BICCN embraces the existing effort of the research community (e.g., the International Neuroinformatics Coordination Facility) to collaboratively build up brain atlases with broadly accessible common brain coordinate systems to integrate and disseminate the brain cell census data. Thus, this FOA supports the development and use of common brain coordinate systems to maximize data and resource sharing. Accordingly, the NIH expects that imaging based cell census data will be registered to common coordinate systems, which include in situ hybridization, immunohistochemistry, cell morphology, and neuronal connectivity mapping. When non-imaging-based approaches are used, applicants should spatially assign the data to the brain regions as accurately as possible. For example, microdissection and computational tools may help map single cell sequencing data onto a reference brain atlas spatially.

Much progress has been made to develop and implement common coordinate systems for human brain (e.g., Allen Human Brain Atlas, BigBrain, BrainSpan,Talairach Coordinate System, MNI Coordinate System) and image segmentation and registration tools (e.g, Insight Segmentation and Registration Toolkit (ITK)) that allow individual labs to integrate their data to the common coordinate systems.

This FOA is related to the implementation of the recommendations under priorities "1. Discovering Diversity" and "2. Maps at Multiple Scales" in the BRAIN 2025 report and The BRAIN Initiative 2.0: From Cells to Circuits, Toward Cures report by the BRAIN Advisory Committee to the NIH Director working groups.

Research Objectives

The purpose of this FOA is to accelerate the use of scalable technologies and tools to enhance brain cell census research, including the development of technology platforms and/or resources and the generation of a large amount of spatiotemporal cell census data and/or resources..

Cell types have been increasingly defined by their location, morphology, connectivity, neurotransmitter type, lineage, function, and most recently, their transcriptomic and epigenomic profiles. Despite a general challenge in defining and distinguishing a cell type from a cell state due to the physiological variability and plasticity of a cell, there is general agreement that cell types can be defined provisionally by stable and generally intrinsic properties of a cell, including (1) molecular signature (e.g., transcriptome, epigenome, proteome, metabolome), (2) anatomy (e.g., location, size, orientation, morphology, and connectivity), (3) function, and (4) development (e.g., trajectories, lineage relationships). This definition of a cell type can provide a good starting point for a systematic cell census, and a foundation for understanding how brain cells are organized and connected as the source of perceptions, actions, and memories. Recent rapid technological advancements enable the possibility of a large-scale brain cell census in mammalian brains. However, there still exist multiple technology and resource gaps and roadblocks that limit the capability, the breadth, and depth of the current brain cell census research. This FOA solicits applications to overcome these shortcomings and aim for a comprehensive and complete analysis of cell properties, neuronal connectivity, and intercellular communication in human, non-human primate, and mouse brains. The projects are expected to augment the ongoing systematic collection and integrative analysis of cell census data by the BICCN.

Tools/technologies and studies relevant for this initiative should be scalable and are expected to significantly improve the technical performance including throughput, sensitivity, selectivity, spatiotemporal resolution and robustness. Of interest are those tools/technologies that have potential to enable comprehensive and complete cell census research for human, non-human primate, and mouse brains. In particular, the FOA supports (a) improving technology and resource platforms to remove limitations and bottlenecks in the current pipeline of brain cell census data generation; (b) generating a substantial amount of spatiotemporal cell census data and/or resources; (c) integrating experimental and computational methods to enhance capabilities of cell census data generation and analysis and to reduce barriers to hypothesis-driven research; and (d) conducting comparative studies by using proper criteria to evaluate and benchmark quality of biospecimen, performance of cell census tools/technologies, and effectiveness of computational approaches. Applications are expected to address limitations and gaps of existing technologies/tools and cell census research as a benchmark against which the improvements or competitive advantages of the proposed ones will be measured.

Examples of scalable tools/technologies of interest and studies include but are not limited to:

(1) Molecular profiling

• high-throughput transcriptomics, epigenomics, proteomics, and/or metabolomics to enable large-scale cell census in a comprehensive manner
• brain cell sorting technologies to enable enrichment of rare cell types and single-cell omics characterization of brain cell diversity at high resolution
• highly sensitive and accurate -omics assays to enable detailed high-resolution analyses of complete molecular signatures
• multiplexed imaging-based spatial profiling of RNAs, DNA methylation and chromatin states, proteins, and/or metabolites in individual cells across whole brain
• simultaneous detection and assay of multiple biomolecule species (e.g., imaging both RNAs and proteins in same cells)
• spatial -omics methods to acquire both cell type molecular signatures and 3D cell location and morphology
• generation of cell census tools and reagents including protein capturing reagents (e.g., monoclonal antibodies, recombinant antibodies, nanobodies), labeling reagents (e.g., super bright dyes), molecular markers (e.g., nucleic acid scaffolded sensors)

(2) Cell morphology

• approaches that will improve the throughput and accuracy of single cell morphology reconstruction in combination with molecular annotation of cell types
• approaches to brightly labeling whole neuron morphology including dendritic and axonal terminals with adequate neuronal density
• implementation of high-throughput, high-resolution, and brain-wide imaging in human and non-human primate brains
• computational methods for defining, quantifying, comparing, and classifying topographic and topological features of cells
• implementation of computational approaches for digital reconstruction, analysis, and 3D brain mapping of single cell morphology

(3) Neuron connectivity and intercellular communication

• comprehensive mapping of neuron connectivity and other intercellular communication modalities including synaptic and neuron-glial interactions at subcellular resolution
• high resolution imaging of cellular structural components including dendritic spines, synaptic junctions, neuron-glia junctions, extracellular matrix, axons, dendrites, and soma
• improved synaptic and trans-synaptic markers, viral and non-viral tracers for antero-, retro-grade, and/or trans-synaptic tracing
• improved labeling tools and technologies to visualize neuron synapses and intercellular communication molecules and structures
• comprehensive mapping of chemical and electrical synapses and other intercellular communication types including that mediated by peptide ligands and their cognate receptors
• implementation of improved computation approaches for the image processing, segmentation, analysis, 3D brain registration, and data annotation
• cross-scale and cross-modality neuron connectivity and intercellular communication mapping and analysis to link molecular cell types to circuits and physiology

(4) Cell lineage and development

• implementation of high-throughput methods for a comprehensive characterization of molecular and anatomical signatures of brain cells at different developmental stages
• systematic study of developmental cell types and lineage relationships combining single-cell omics and lineage tracing methods in human, mouse, and non-human primate brains
• tools for multiplex lineage marking and readout in combination with massively-parallel genetic screens or manipulation of different functional properties
• implementation of computation approaches to analyze, integrate, and map the developmental brain cell census data to 3D common coordinate frameworks

Applications funded under this FOA are expected to align their specific aims with the overarching goal of the BICCN to generate comprehensive 3D common reference brain cell atlases that will integrate molecular, anatomical, functional, and cell lineage data for describing cell types in mouse, human, and non-human primate brains. The awardees are expected to generate a substantial amount of cell census data and/or resources during the project period using the proposed technologies or via collaboration with the BICCN and are expected to follow the BICCN's resource and data sharing policy.

Milestones and timelines: The success of the project will be facilitated by the adoption of clear, quantitative milestones with realistic and efficient timelines. Applications are expected to include annual milestones with metrics that will document progress towards the achievement of the specific aims. Milestones should be well described, quantifiable, and scientifically justified benchmarks. The milestones should be regarded as criteria for evaluating the progress and direction of the project and should not be just a restatement of the specific aims. During the project period, the awardees will be expected to refer to these milestones in progress reports. The funding institute will use the milestones, the progress reports, and other measures of productivity and success to judge the progress, impact, and value of the program. To ensure comprehensive coverage of cell diversity and avoid overcommitting resources to a limited number of brain regions and cell types, the NIH program staff may consider portfolio balance when making funding decisions and negotiating the milestones.

Applicants are strongly encouraged to consult the appropriate Scientific/Research Contact, listed below, to discuss the alignment of their proposed work with the goals of this FOA and BRAIN Initiative Program.

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Governments

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Applications Involving the NIH Intramural Research Program

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the NIH Intramural Program. NIH intramural scientists will participate in this program as PDs/PIs in accord with the Terms and Conditions provided in this FOA. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above.

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: Describe overall research aims and strategy. Among the proposed specific aims, include one aim to generate a substantial amount of cell census data using the proposed technologies or via collaboration with the BICCN to demonstrate the utility and performance of the technologies.

Research Strategy:

Describe how the project will align with the overarching goals of the BRAIN Initiative Cell Census Network (BICCN) to generate comprehensive 3D common reference brain cell atlases that will integrate molecular, anatomical, functional, and cell lineage data for describing cell types in mouse, human, and non-human primate brains.

Describe limitations and gaps of existing technologies/tools and cell census studies as a benchmark against which the improvements or competitive advantages of the proposed ones will be measured. The improvements include throughput, sensitivity, selectivity, scalability, spatiotemporal resolution and reproducibility in cell census analyses.

For the data generation the applications are expected to:

• describe tissue collection approaches to ensure the high quality of the brain tissue specimens;
• describe research theme(s);
• describe the brain samples and structures/regions to be analyzed;
• describe preliminary data and tool generation effort and the state-of-the art approaches used;
• provide estimates of data quality and plans for how data quality will be evaluated;
• describe how to optimize experimental procedures to reduce technical noise and enhance data quality;
• describe workflow including throughput as well as rate-limiting steps, and provide plans for assessing and improving the pipeline;
• describe quality control/quality assurance measures and decision making process;
• describe anticipated cost reductions with a cost model incorporating a standardized cost structure including a useful unit (e.g., per experiment or per cell characterized) and identify large-cost items that dominate the cost model;
• describe innovative aspects of the project.

Describe Milestones and timelines: Applications to this FOA are expected to define a clear set of overall goals that are aligned with the BICCN’s goals, and include annual milestones with metrics that will document progress towards the achievement of the overall goals. For each approach, clear, quantitative outcomes should be set and described. Annual milestones include plans for critically evaluating and revising these milestones on a regular basis.

Letters of Support: Include letters of support/agreement for any collaborative arrangements, subcontracts, or consultants. Letters of support should indicate the specific activities the individual or organization will perform in pursuit of the goals; letters of support from individuals or organizations without a specific role in the project should not be included.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

The following modifications also apply:

A central goal of this FOA is to build up a comprehensive brain cell census data resource that will be widely used throughout the research community. It will take the combined resources of researchers in the public and private sectors many years to catalog and characterize the biology of brain cells, neuronal connectivity of interest, to understand brain function, and then to use that information to improve public health. The open sharing of the brain census data, research tools, and resources will not only lead more rapidly to their broad use by the research community, but also encourage scientific rigor in data production and analysis, with resulting benefits to public health. In order to reap the maximum value from this program, all molecular, anatomical, and physiological data, experimental protocols, and tools generated are expected to be made publicly available. Awardees will be subject to the Data Sharing Policy for the BRAIN Initiative (NOT-MH-19-010). Applications must include a detailed plan for sharing data and resources and include the following key elements:

• Project management of data and resource sharing;
• Description of what specific data and resources will be shared (e.g., single cell transcriptome data, immunohistochemistry data, cell morphology data, neuronal connectivity data, electrophysiological data, functional connectivity data, software, model organisms, reagents, completed tools or repurposed components);
• Schedule/timeline for availability of data and resources to other users.

Data Sharing. Applicants must provide a specific proposal for data sharing in the application, and address the issues related to the public release of data and data analyses (see the rationale for FAIR (Findability, Accessibility, Interoperability, and Reusability) Data Principles). After the initial review, the BRAIN program staff will be responsible for any additional administrative review of the plan for sharing data and may negotiate modifications of the data sharing plan with the prospective awardee prior to award. The final negotiated version of the data sharing plan will become a term and condition of the award. The BICCN Steering Committee, of which all awardees will be members, will develop a final, common data release plan as appropriate for the project that will address the interests of the data producers and analysts, as well as the users of the BICCN brain cell census atlases. Applicants should indicate their willingness to participate in the development of such a final plan and to accept it. The NIH expects that verified raw data will be submitted in real time or other agreed-upon timeframe depending on the data types and verification requirements to long-term publicly accessible archives such as GEO or others as appropriate. Applicants should address whether they anticipate any of their data will require controlled access. Agreement to abide by that policy is a requirement for anyone to join the Network.

Resource Sharing. As the BICCN is generating a community resource, in addition to data, resources generated by the BICCN projects should be made rapidly available to the research community. Rapid dissemination of these resources would accelerate scientific exploration and avoid duplicative resource development effort. The applicant should provide specific plans for resource sharing and distribution in the application. After the initial review, the BRAIN program staff will be responsible for any additional administrative review of the plan for sharing resources and may negotiate modifications of the resource sharing plan with the prospective awardee prior to award. The final negotiated version of the resource sharing plan will become a term and condition of the award. will become a term and condition of the award of the cooperative agreement.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Will the proposed aims and scientific questions facilitate the generation of comprehensive 3D common reference brain cell atlases that will integrate molecular, anatomical, functional, and cell lineage data for describing cell types in mouse, human, and non-human primate brains?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Are the PD/PI and other key personnel devoting sufficient time/effort to achieve the goals?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Does the application address limitations and gaps of existing technologies/tools as a benchmark against which the improvements or competitive advantages of the proposed ones will be measured?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Does the proposed approach accelerate the integration and use of scalable technologies and tools to enhance brain cell census research, including the development of technology platforms and/or resources and the generation of spatiotemporal cell census data and/or resources? Does the proposed approach address improvements to throughput, sensitivity, selectivity, scalability, spatiotemporal resolution or reproducibility in cell census analyses?

For this specific FOA: Evaluate the plan for building a comprehensive brain cell census data resource to use throughout the research community. How adequate are the plans for sharing data and resources (e.g., project management of data and resource sharing, description of specific data and resources to be shared, schedule/timeline for availability of data and resources to others)? Does the proposed plan for open sharing of the brain census data, research tools, and resources provide adequate capacity to encourage scientific rigor and lead to broad use by the research community? Are the overall proposed data sharing plan and the issues related to the public release of data and data analyses feasible and appropriate to achieve the BICCN goals? Does the resource sharing plan provide adequate capacity and ability to share and distribute resources rapidly?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Milestones and Timelines

Are clear, quantitative, and actionable, milestones and timelines proposed? Do the milestones establish feasibility for all aspects of the proposed research? Does the application include plans for critically evaluating and revising milestones on a regular basis? Are there additional key experiments that need to have milestones? Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIMH, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities
• Programmatic balance. The purpose is to develop a portfolio with complementary capabilities towards generating a comprehensive brain cell atlas. Therefore, decisions about awards will consider the mix of capabilities offered by the proposed projects.

3. Anticipated Announcement and Award Dates

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

• Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Not Applicable

3. Reporting

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Yong Yao, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-6102
Email:[email protected]

Nick Gaiano, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-827-3420
Email: [email protected]

Tamara Kees
National Institute of Mental Health (NIMH)
Telephone: 301-443-8811
Email: [email protected]

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.